(1 ) Field of the Invention
The present invention relates to a method and compositions for the treatment of malignant tumors or metastasis of malignant tumors by administering a platinum coordination compound and a calcium channel blocker compound of the dihydropyridine class. In particular the present invention relates to a method which comprises administering cis-diamminedichloroplatinum (II) and nifedipine, respectively, as the compounds.
(2 ) Prior Art
Cis-diamminedichloroplatinum (CDDP, cisplatin) is the first inorganic antitumor agent used for clinical cancer therapy. Developed and first described by Rosenberg et al (Nature 205:698, (1965); Nature 222:385, (1969)), cisplatin has proven to be an effective antineoplastic agent not only against germinnal neoplasms as it was first utilized (Einhorn et al., Int. Med. 87:293, 1977 ) but also against bladder and ovarian cancer and cancer of the head and neck. It is possible that cisplatin alone or cisplatin in combination with other antineoplastic drugs (e.g, adriamycin, vincristine, etc.) may become the accepted standard agent for the chemotherapeutic treatment of a majority of malignancies including those which are usually considered non-responsive to chemotherapy, such as estrogen resistant prostate carcinoma (Merrin, C. E., Cancer Treat. Rep. 63:1579, 1979). This and other platinum coordination compounds are shown in U.S. Pat. Nos. 4,140,707, 4,177,263 and 4,419,351 for instance.
Unfortunately, the development of cisplatin resistance in malignant tumors which initially responded to cisplatin is an all too often encountered problem (Lee et al., Cancer Treat. Rev. 10:39, 1983 ). As with other chemotherapeutic drugs, cisplatin resistance of the primary tumor and recurrent metastases prevents cisplatin chemotherapy from achieving partial or complete remission rates of more than 15% to 70% for testicular cancer (Stoter et al, Cancer 54:1521, 1984 ), and ovarian cancer (Belinson et al., Cancer 54:1983, 1984 ), and 30-40% for cancer of the head and neck (Wittes et al., Cancer Treat. Rep. 63:1533, 1979).
The most serious problem encountered in the chemotherapeutic treatment of cancer is the presence and/or the development of drug resistance by cells of the primary tumor. If the patient dies of metastatic cancer, the cells of the metastatic foci are usually also characterized by their extreme resistance to single or combinations of the available chemotherapeutic drugs. In general, drug resistant tumor cells simply accumulate less (a sublethal dose) of the chemotherapeutic drug(s) than do cells which succumb to the therapeutic agent. Drug resistant tumors can be classified as temporary or permanent (DeVita, V. T., Cancer 51:1209, 1983). Temporary drug resistant tumors are thought to be resistant as a result of physiological factors such as sublethal exposure to drug by tumor cells distant from circulation (i.e., perfusion barrier; Sutherland, R. M., et al., J. Nat. Cancer Inst. 46:113, 1971; and West, G. W., et al., Cancer Res. 40:3665, 1980). Additionally, it has been suggested that the overall growth kinetics of the tumor (Shackney, S.E., et al., Ann. Int. Med. 89:107, 1978) are an important factor in temporary tumor cell resistance (i.e., slowly or asynchronously growing tumor cells would be less likely to be exposed to (accumulate) bolus injected anticancer agents). Permanent drug resistant tumor cells are thought to arise spontaneously, and their probability of existence may be related to tumor mass and/or age. The concept of the spontaneous genetic orgin of drug resistant neoplasms (Goldie and Coldman, Cancer Res. 44:3643, 1984) and tumor heterogeneity in terms of metastatic potential (Fidler, I. J., Cancer Res. 38:2651, 1978) and drug sensitivity (Tanigawa, N, et al., Cancer Res. 44:2309, 1984), has gained widespread acceptance as the mechanism of permanent tumor cell resistance. The two principal mechanisms of permanent drug resistance have been found to be mediated by changes in the concentration or activity of an enzyme in the resistant cells that "inactivates" the drug (Bakka, A., et al., Toxicol. Applied Pharmacol. 61:215, 1981) or by changes in the plasma membrane of the resistant cells which decreases cellular accumulation of drug by inhibiting drug influx and/or by increasing the rate of drug efflux (Giavazzi, R, et al., Cancer Res. 43:2216, 1983; Yanovich, S., et al., Cancer Res. 44:1743, 1984).
Initial attempts to circumvent drug resistance centered on alterations in the scheduling, dosages, and/or method of application of a single chemotherapeutic agent (Benz, C., et al., Cancer Res. 42:2081, 1982; Ozols, R. F., et al., Cancer Res. 42:4265, 1982). Much more promising, however, appears to be combined drug therapy using cytotoxic agents with different mechanisms of action. This type of therapy has improved the cure rate for some cancers but the ultimate failure of even this strategy is well documented (Ling, V., et al., Cancer Treat. Rep. 67:869, 1983; Citrin, D. L., et al., Cancer 50:201, 1982).
Recently, a new methodology has been suggested which may be of great benefit in the chemotherapeutic treatment of cancer. This methodology is centered on the use of agents which function to enhance the initial kill-rate of a cytotoxic drug and/or which enhance the ability of the drug to overcome drug resistant tumors.
Inaba, M., et al., Cancer Res. 39:2200, 1979 reported that the significantly decreased uptake and retention of adriamycin and daunorubicin by P388 leukemia cells resistant to these agents was mediated by an active outward transport of the two cytotoxic agents by resistant cells. These findings suggested that membrane active compounds might be utilized to overcome the outward transport of cytotoxic agents from resistant tumor cells. Riehm and Biedler (1972) reported that they were able to overcome actinomycin D resistance in Chinese hamster cells by treatment with the detergent Tween 80. Subsequently, Valeriote et al (V-aleriote F., et al., Cancer Res. 39:2041, 1979) reported that the membrane active antibiotic amphotericin B was able to enhance the effects of adriamycin and vincristine against AKR leukemia. Tsuruo et al (Cancer Res. 41:1967, 1981) introduced the use of a calcium channel blocker of the phenylakylamine class (verapamil) to overcome vincristine resistance in P388 leukemia in vitro and in vivo. Tsuruo's subsequent reports (Cancer Res; 42:4730; 43:2267 and 44:4303, 1982, 1983c, 1984, respectively) and those of other investigators have clearly established the utility of verapamil (Slater et al, J. Clin. Invest. 70:1131, 1982) and other calcium regulatory compounds (Ganapathi et al, Cancer Res. 44:5056, 1984) as enhancing the cytotoxic effect of these anticancer agents against drug resistant tumors.
It has been demonstrated that verapamil is able to decrease the efflux of adrimycin, vincristine and daunorubicin from untreated and resistant tumor cells. This results in an increased effective intracellular accumulation of the cytotoxic agent and results in a decrease in the LD50 concentration of the antitumor agent. The ability of daunorubicin resistant and sensitive Ehrlich ascites carcinoma cells to accumulate and retain daunorubicin is inversely related to the concentration of Ca.sup.2+ in the incubation medium (Murray et al, Cancer Chemotherap. Pharmacol. 13:69, 1984). Verapamil's ability to increase daunorubicin cytotoxicity in resistant Ehrlich tumor cells may be at least partially attributable to its (verapamil) abiltty to inhibit calcium influx, which would have effects similar to those obtained by decreasing extracellular Ca.sup.2+.
The cytotoxic mechanism of action of cisplatin is known to be its ability of the platinum moiety to form DNA-DNA and DNA-protein crosslinks in the target cell nucleus, thus preventing new mRNA transcription and DNA replication (Roberts, J. J., In: Molecular Actions and Targets for Cancer Chemotherapeutic Agents, Academic Press, New York, p. 17, 1981). The exact mechanism of resistance to cisplatin, however, is not known (Curt et al, Cancer Treat. Rep. 68:87, 1984). Sigdestad et al (Cancer Treat. Rep. 65:845, 1981) reported that all phases of the cell cycle (G1, S, G2 and M) of a murine fibrosarcoma were sensitive (in vivo) to cisplatin although cells in the G1 phase were the most sensitive by a factor of 10. This data suggests that slowly growing cells or asynchronously growing tumor cells might be the population of cells that eventually demonstrate cisplatin resistance. Whether the growth rate or phase of cell cycle affects enzyme activity or the membrane of resistant cells (as the basis for cisplatin resistance) is not known.
Because of this lack of understanding of the mechanism of cisplatin resistance, attempts have been made to bypass the problem of cisplatin resistant tumor cells by the development of cisplatin analogs, which are now in clinical trials. Unfortunately, many of the analogs are no more tumoricidal than cisplatin and thus the possibility of resistant tumor populations surviving drug treatment and thus proliferating still remain (Rose et al., Cancer Treat. Rep. 66:135, 1982).
Few investigators have examined the ability of non-chemotherapeutic agents to enhance the antineoplastic effects of cisplatin, perhaps because the mechanism of cisplatin resistance remains unknown. Misonidazole, a radiation sensitizer, was found to enhance the cytotoxic effect of cyclophosphamide and L-phenylalanine mustard but not cisplatin, when tested against the murine reticulum cell carcinoma M5076 (Clement et al, Cancer Res. 40:4165, 1980). In an earlier study using cultured HeLa cells and mouse FM3A cells, verapamil enhanced the cytotoxic effect of peplomycin (a member of the bleomycin group of antibiotics) but failed to enhance the cytotoxic effects of cisplatin (Mizuno and Ishida, Biochem. Biophys. Res. Commun. 107:1021, 1982).
Tsuruo et al (Cancer Res. 41:1967,(1981)) demonstrated in vitro that the calcium channel blocker verapamil enhanced antitumor drug effects against normal and drug resistant murine tumors (Tsuruo et al, Cancer Res. 2:4730, 1982). This enhancement of antitumor drug effect by verapamil appears to be relatively non-specific in that verapamil enhances both vinca alkyloid (Tsuruo et al, Cancer Res. 43:808, 1983a) and anthracycline antibiotic (Tsuruo et al, Cancer Res. 43:2905, 1983b) cytotoxic effects. The ability of verapamil to enhance cytotoxic drug effects is not limited to murine tumor cell lines. Rogan et al (Science 224:994,(1984)(1981) has demonstrated that verapamil overcomes adriamycin resistance against a cultured human ovarian tumor cell line and Tsuruo et al (Cancer Res. 43:2267,(1983c)) reported that verapamil potentiated vincristine and adriamycin effects against human hemopoietic tumor cell lines.
Few investigators have addressed the question of enhancement of antitumor drug effects by calcium channel blockers (CCB) or other membrane active compounds in vivo against normal or drug resistant tumor cell lines. Tsuruo et al (Cancer Res. 41:1967, 1981 and Cancer Res. 43:2905, 1983b) has reported that vincristine and adriamycin resistance in P388 leukeumia can be overcome by verapamil in vivo. Unfortunately the P388 leukemia is an ascites tumor, not a solid tumor, and in humans the majority of fatal malignancies are solid tumors and/or their metastases. Akagawa, S., et al, Kagaku Nyoko 11 943-7 (1984) describe using nicardipine with vindesine sulfate and dichloroplatinum II in the treatment of drug resistant esphageal carcinomas in humans. A partial response was achieved. Akazawa, S. et al found that large dosages (500 nanograms per ml in the blood stream) appeared to enhance the effects of vindesine sulfate (VDS) and diamine dichloroplatinum (II) (CDDP) in treating an esophageal carcinoma. There appeared to be regression of various tumors as a result of the treatment; however, the effective dosage of the nicardipine was large and lower dosages were uneffective. The purpose of the experiment was to enhance the effect of the VDS and not the CDDP.
It has been found, as disclosed in Ser. No. 80,704, that CCB of the dihydropyridine class are more potent in their antimetastatic effects than verapamil. Kessel and Wilberding (Biochem. Pharmacol. 33:1157, 1984) found that verapamil and nitrendipine (a dihydropyridine class CCB) exhibited different modes of action in mediating accumulation of daunorubicin in P388 and P388/ADR resistant cells in culture. Verapamil showed superior ability to enhance the accumulation of daunorubicin in normal cells as compared to resistant cells. In contrast, nitrendipine enhancement of daunorubicin accumulation was identical in both P388 cell lines. Additionally, nitrendipine's ability to enhance the accumulation of daunorubicin in both tumor cell lines was greatly superior (in micromoles) to that of verapamil. Thus independent investigators support the previous published work of Honn et al that the calcium channel blocker compounds of the dihydropyridine class are superior anticancer properties to verapamil. However, there has been no suggestion in the prior art that low dosages of selected calcium channel blockers can be used with a platinum coordination compound for the reduction of metastasis or for the regression of tumors.